Oral ganciclovir (CytoveneTM )(OG) has been evaluated both for prevention (prophylaxis) of primary and secondary cytomegalovirus (CMV) infection (new and recurrent infections, respectively). OG received FDA approval in 1994 for maintenance therapy following CMV infection (reducing risk of recurrence). Until now, there was no effective prophylaxis against CMV in high risk HIV-positive individuals (less than 50-100 CD4 cells). CMV infection may result in ocular disease (infection inside the eye, retinitis) or extraocular disease (primarily gastrointestinal and CNS (brain) infection). Additionally, due to the high risk of recurrent infections, persons with CMV infection must stay on some form of therapy to decrease the risk of recurrent disease.

A recent study compared intravenous and oral ganciclovir as maintenance treatment for persons with CMV retinitis.1 Oral ganciclovir was found to be "safe and effective as maintenance therapy" for CMV retinitis. The treatment for a new CMV infection still requires intravenous drug therapy though. There was a higher recurrence rate in the oral therapy group in this trial, particularly when progression was measured by objective retinal photography. However, by clinical assessment, the time to progression was 96 days in the intravenous group versus 68 days in the oral group. The authors did emphasize the convenience of the oral form for the people in the trial.

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Syntex conducted a trial evaluating OG for primary prophylaxis of CMV infection in 725 people. The study treated 2/3rds of the participants with OG, 1000 mg 3 times a day, and 1/3rd received a placebo. Participants all had positive CMV serology (antibodies to CMV) or positive CMV cultures. Eligibility included a CD4 count of 50 or less, or a CD4 count of 100 or less and an AIDS-defining opportunistic infection. (Almost all persons (95%) with CD4 counts <100 have CMV antibodies or positive cultures.) The study was stopped early because there was a 49% decrease in the number of clinical CMV infections in the group which received OG. There was a significant decrease in the incidence of ocular disease (retinitis). Extraocular disease was decreased as well but the number of cases were too small to achieve statistical significance. The group which received OG did have a higher incidence of low white and red blood cell counts (neutropenia and anemia), so blood counts must be followed regularly in persons receiving OG. This is the study which led the FDA to approve OG for use in primary prophylaxis this past month. However, a multi-center study was presented at the ICAAC Conference, September 1995 (Abstract #LB-10) with conflicting results. A total of 994 persons with CD4 <100 cells and either a positive CMV serology (antibodies to CMV) or culture, but without CMV disease, were randomized to either placebo (332) or oral ganciclovir (1000 mg tid)(662). However, due to the report by Syntex after the trial began, persons in the placebo group were allowed to switch to the treatment group. Thus, the analysis presented was based on an "intention to treat" method. There was a higher incidence of neutropenia (low white blood cell count) in the group which received oral ganciclovir. This study did not find a benefit (fewer new CMV infections) in the group which received oral ganciclovir. This study did not use retinal photography to evaluate retinal CMV infection, as the Syntex study did. Also, OG does not absolutely prevent CMV infection, rather it appears to delay the appearance of CMV infection, so a study result is dependent on the time intervals of the analysis. (Even if CMV infections are only delayed by the use of OG, this is a significant benefit due to the risk of loss of sight associated with CMV retinitis.) Additionally, the intention to treat analysis may "mask" a benefit of OG since many of the people analyzed in the placebo group actually received OG, as they were allowed to cross over to the treatment group early in the study.

A potential complication of the use of oral ganciclovir for primary prophylaxis is the development of resistance. A study reported at the ICAAC Conference, September, 1995, by Syntex, identified this as potential but infrequent occurrence. Resistance to oral ganciclovir was observed in only 1% of the isolates after 10 months of therapy.

The cost of intravenous and oral ganciclovir was compared in a presentation at the ICAAC Conference, September, 1995. The daily cost of oral ganciclovir was $46.80, compared to $40.61 for the intravenous form. However, the authors noted that the cost may be less for the oral form if the efficacy is similar and the costs of central catheter placement and catheter infection complications are considered.

The approval of OG for CMV prophylaxis is a significant step in reducing a common and serious sight-threatening and life-threatening disease in persons with CD4 cell counts below 100.

Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee

Nutrition Power® " Upside-Down"

Note: 1/250 Americans is estimated to be HIV+. This number is used here.

Also, this article is about suitable nutrition principles for most people with HIV/AIDS. If you are in doubt, consult with your physician or nutritionist.

Fascinating Facts: Studies confirm that when living with HIV/AIDS, those who change their diets use guidelines recommended for the prevention of other diseases like heart disease and cancer. Don't misunderstand -- prevention of these maladies is very important. But, with HIV/AIDS, there is little increased risk of either, except for immune-related Kaposi's Sarcoma (KS) and Lymphomas.

Another fascinating fact: Cholesterol, the nemesis of middle-class America, is the last thing most people with HIV/AIDS need to worry about -- that is, if it doesn't drop too low! That's right; cholesterol has been used in many scientific studies to monitor nutritional status of HIV/AIDS, and decreasing numbers are often not a good sign.

Further fascinating fact: Heart-healthy aerobic exercise, while important for everyone's health program, is not to be overdone; it's important to emphasize muscle-building exercises like lifting weights and other resistance work.

So, when deciding how to conduct our nutritional selves, we'll read advice in magazines and newspapers, see it on TV, hear it on radio, and overhear gossip. Do you think these communications are targeted to HIV-positive America? No Way!

What everyone reads and hears about is diet advice for middle-class, "Norman Rockwell," America. We hear that a diet high in saturated fat, for example, is bad because it raises blood cholesterol. The HIV/AIDS counterpoint is that some saturated fat such as medium-chain triglycerides (MCT) can be the perfect fat type for us -- and MCT is totally saturated! Coconuts are full of MCT; in fact, their milk and flesh are almost all fat and it's 97% saturated! A heart patient could have a coronary just looking at coconuts!
Remember, 249 of 250 Americans are HIV-negative. The only place you'll get HIV-specific and current nutrition advice is from newsletters like this (a book would be outdated before it ever got to press!). And that's why I call this "upside-down." Take what you read in the "popular press," and almost always do the opposite -- from diet to exercise.

I keep indulging in "salad bashing" -- it's so easy! Take the common leafy salad. For the 249/250 people who may need (or want) to lose weight, salad is a perfect food. It has no significant nutrient value, almost no calories, and with low- or non-fat dressing, it's really just a "flavor carrier." That salad has very few calories and takes a long time to eat. Also salads contain "roughage" for promoting easier, quicker bowel movements. Upside-down!

There's still that 1/250 who generally don't need or want to lose weight. You've heard of "empty calories," salads are "empty food." Lettuce (including Romaine) has almost no nutrients. It gets worse. Lettuce packs in water, holding the fluid between its plant cell walls. This watery appetizer, which gets squashed when you chew, can contribute to the "feeling-full-too-fast" syndrome. And those plant cells are pure roughage; enough to make a bad case of diarrhea worse, and cause a good case of diarrhea for those lucky enough not to have it. Also, since salads do take time to eat, energy could be wasted doing unnecessary work. Good for the majority, not good for those of us who are not constipated! Upside-down.

But there's an even more important, and probably less well recognized problem with salads: Hard-to-clean salad greens! (Ms. Food Safety strikes again!) No matter what you do, or how hard you try, you're not going to get those greens totally clean. Healthy immune systems are fine with a little dirt; unhealthy ones are at risk. And for eating out, perhaps a machine washed the lettuce well, but servers handling the lettuce may only wear those cute little plastic gloves when in public; behind the scenes, who knows? Worse yet, have you ever been to a salad bar where there's a plate of glass to shield the buffet from your breath -- they're called "sneeze-guards" for a reason!

Salads gone, let's take on "the beef!" There are some outstanding nutritional benefits in the meat group, red meat in particular -- for HIV/AIDS nutrition healthcare. The heart-risk patient would be told to eat less red meat and more white-meat chicken. That's exactly what I would tell a normal HIV- negative person with high cholesterol. Remember, cholesterol is more risky when it's too low -- separating HIV/AIDS (1/250) from the majority (249/250) of Americans. Upside-down again.

The reason that HIV-negative America is told to eat less meat is because of the fat and cholesterol. For this the no red-meat "rule" was devised. But for HIV/AIDS, red meat is not only a good protein provider, it's also a natural way to acquire iron, zinc, vitamin B-6. In fact, even beef liver, really high in cholesterol, minerals and B-vitamins, is very low in fat and another good food choice for the HIV/AIDS diet.
And to settle a recent issue of mine: An HIV nutrition handbook warned against all kinds of meat, pork in particular. While I have no quarrel with Biblical law as practiced then, I must carefully point out that pork is our very very best source of vitamin B-1 (Thiamin), necessary to digest carbohydrates. A recommended starch intake is about 60-70% of all food eaten so this vitamin is important. Yes, it is available in other foods, but -- it's awesome in pork.
Since those old pork rules had mainly to do with food safety, I'll just grab another chance to warn everyone (regardless of HIV status) to cook food well. Since heat kills germs, and modern refrigerators prevent spoilage (aka "oxidation," a different article), all that is necessary to avoid food-borne infection is to cook food very well-done, especially ground meats where every morsel -- not just the surface as in a steak -- may carry deadly bacteria. Just three words: Heat Kills Germs!

I also want to tackle, albeit briefly, the issue of animal protein versus plant protein. Here are some facts from science. Protein is made of strings of amino acids -- like uneven pearls. When protein pearls are digested, they break down into individual amino acids (22 shapes and sizes), which are sent to the liver and processed into living cells. Amino acids are chemical compounds and are exactly the same whether they come from an animal, a plant or (even) a test tube!

Then, there's the much-maligned EGG. Long out of favor in U.S. diets because yolks are full of cholesterol (whites are cholesterol free), eggs are invaluable for the diet geared toward needs of HIV/AIDS. Since egg yolk cholesterol is no longer bothersome, let's consider the white: Pure protein, and the standard by which all other proteins are judged. My advice: "Eat eggs" (well cooked, please!).

Having dispensed with salads, red meat, liver, pork, protein source and egg conflicts, let's tackle just two more items in the Norman Rockwell diet. How about fiber? Since the American public eats only about 11 grams of fiber per day, but is advised to get from 30-40 grams/day (to prevent heart disease and some cancers), the high-fiber diet is heavily promoted amongst healthcare professionals.

Sometimes, as with salads, that fiber may not be such a good idea, due to diarrhea. But, remember, 249/250 Americans want and need more fiber -- they're constipated! Package labels are not only informative, they're downright boastful on the fiber content. Avoid these high-fiber foods if diarrhea is a concern. Here again, it's upside-down on the advice for the public (increase fiber) as opposed to advice for that special 1/250th person (decrease fiber).

Now for exercise! Since HIV- America generally wants to lose weight, high-level aerobic exercise is recommended -- often multiple workouts per day of panting/sweating exercise. For HIV+ America, the minority, that kind of intensity may burn calories unnecessarily. There's always a place for "some" aerobic work, but the major focus of exercise for HIV/AIDS must be geared to resistance training: weight-lifting. Adding muscle seems to afford some protection from wasting (a future article).

The HIV-infected body is different from others. Since weight loss is usually more of a problem than a desire, unnecessary calorie burning needs to be kept to a minimum, while adding muscles, for that so-called "lean mass" is emphasized. Thus, the weight training and muscle building should be emphasized.
These exercise guidelines are very general because I am not, and never will be, an exercise physiologist. How we spend our energy (calories) is just as important as the kind of energy we take in (food). For that, I suggest that the next step towards a maximum, "personal-best" result: consult a fitness instructor or exercise physiologist for an exercise plan. That is . . . after you have your nutrition in order!

I'm a nutritionist. I know more nutrition than I'll ever be able to teach, and I love what I do. Nutrition is my area of expertise, and I'm good at it. Nutrition should be included as a co-therapy with medical regimens. Nutrition is powerful and that's why I call it Nutrition Power®. Healing the body without care for what nourishes it is doing only part of the job.

As always, if this advice causes, or seems to cause, adverse symptoms, contact your doctor or dietitian. The advice in this column is not geared toward heart patients. Always check with your doctor if you re not sure.

Jennifer Jensen, MS, RD is in private practice, and serves as nutritionist for Project Angel Food. She offers a sliding scale for HIV/AIDS consultations. Don't be shy -- call her at (310) 450-5581.

Nutrition Power is a registered trademark of Health and Nutrition Awareness. Permission for use, with proper credit, is granted to STEP.

Current Views on Vaccinations

by Jon Hubert, DDS

The first modern use of immunization was by the British physician Edward Jenner in 1796. He used cowpox inoculations to produce protection against smallpox. In 1885 the French scientist Louis Pasteur first used an attenuated or weakened rabies virus to protect against the natural infection, and in 1897 a vaccine against typhoid fever was developed in England.

Immunization, in preventative medicine, is the process of rendering people immune to an infectious organism by inoculating them with a form of the organism that does not cause severe disease but does provoke formation of protective antibodies. The process has also been called vaccination, because the first instance of immunization was the use of vaccinia, the fluid from lesions produced by the cowpox virus in cattle, to produce immunity to smallpox in humans. Vaccines are the most effective protection against most diseases caused by viruses and related organisms because few antibiotics work against them. In Western countries vaccines are routinely used in the first years of life to produce immunity to diphtheria, tetanus, poliomyelitis, and whooping cough. Other vaccines which are used more selectively in adult populations include those for Hepatitis-B (serum hepatitis), pneumococcol pneumonia, and influenza (flu).
The Hepatitis, pneumonia and influenza vaccines may be given to people who are at high risk of being exposed to the disease or to people who might be likely to suffer more severe effects from infection than would the general population due to age immune-compromised status or other medical conditions. The heightened risk of complications following infections is termed increased morbidity in medical terminology. Death rates can also be higher and this is termed increased mortality.

For example, elderly people living in nursing homes are at increased risk for exposure to influenza due to the concentration of people in the facility. They are also more likely to suffer increased morbidity and mortality due to their age and various medical conditions. The elderly are particularly susceptible to bacterial pneumonia following an attack of the flu. It is estimated that more than 10,000 excess deaths occurred during each of seven different US epidemics in the period 1977 - 1988 and 40,000 excess deaths occurred during two of the most severe epidemics during that period. Overall, approximately 80 to 90% of all deaths attributed to pneumonia and influenza occurred among persons over 65 years of age1

Flu vaccines can be up to 80% effective in reducing morbidity and mortality associated with flu epidemics in elderly populations.1 It is on this basis that flu shots are recommended for persons over 65 years of age. Since persons infected with HIV are at risk for severe pulmonary infections caused by the same bacterial organisms that have been associated with influenza, health officials have recommended flu shots to HIV-positive individuals.1,2 There have not, however, been studies that show conclusively that HIV-positive individuals are at higher risk for catching the flu or actually suffering increased morbidity or mortality.1,2

Most of the studies of vaccines that have been done since the mid-80s have attempted to determine if HIV positive people develop adequate antibodies as a result of vaccination. Studies done in 1988 and 1989 showed that a positive response to flu shots occurred in from 50 to 80% of asymptomatic and from 13 to 50% of those subjects who were symptomatic. Seronegative control groups had greater than 95% protective response.2,3,4,5,6,7

There has also been the concern that vaccination could stimulate HIV and thus cause more harm than good. However, no increased in p24 antigen or morbidity or mortality were seen with the flu shots. The authors were aware that p24 antigen levels were not a good measure of HIV activity. Until recently additional research has supported the conclusion that the benefits of flu shots outweighed the possible negative effects. Immunity levels were high with higher CD4 counts, dropping to very low levels with low CD4 counts.8,9,10, 11

Some vaccines require well functioning T-cells to achieve immunity (T-cell dependent) while others do not (T-cell independent). Examples of T-cell dependent vaccines are those for the flu, hepatitis, tetanus. The primary example of T-cell independent vaccine of interest to HIV positive people is the vaccine for pneumonia (Pneumovax). Research has shown that HIV-positive individuals with low CD4 counts demonstrate impaired immunity with T-cell dependent vaccines while the T-cell independent vaccine Pneumovax tends to induce normal antibody formation.5 Further studies have shown that the immunity produced by Pneumovax was generally unrelated to CD4 count,11 although the response was stronger earlier in HIV infection and tended to fall off with advancing HIV disease.12,13 The general conclusion with regard to Pneumovax was that HIV-positive individuals would benefit from vaccination particularly if given early in the course of the disease.

Several recent studies by the VA Medical Centers, West Los Angeles, have raised questions about the potential stimulation of HIV activity that is caused by vaccination. In contrast to earlier studies that relied on p24 antigen and disease progression that asses HIV stimulation, recent studies have measured HIV RNA by PCR (Polymerase Chain Reaction test, a test the measures the amount of virus in your system). A study published in August, 1995, showed a temporary ten-fold HIV level increase in 50 percent of the subjects who received flu shots (20 subjects) while there was no change in the unvaccinated controls (14 subjects). The authors did not see a sustained increase in HIV replication at one month following vaccination.14 The authors felt that an actual flu infection would lead to a greater level of HIV replication than vaccination. They did not attempt to address the appropriateness of influenza vaccination. They did suggest that it would be prudent to administer antiretroviral therapy to all people receiving immunization in order to minimize increases in viral load.

At the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) September, 1995 the same group released data on a follow-up study. They showed similar HIV RNA increases but documented a longer term effect on CD4 than might be expected from their earlier study.

In this double-blinded study, 47 HIV-positive persons were randomized to receive influenza vaccine or placebo. The groups were demographically similar, had no differences in CD4 levels, baseline plasma viremia or antiretroviral use. At one month mean plasma HIV RNA (by quantitative PCR) increased from 23,892 to 135,873 copies/ml in the vaccinated group compared to a slight decline from 25,826 to 18,470 copies/ml in the placebo group. Three months after immunization the CD4 percentage had dropped slightly (-1.8 per cent) in the immunized group and had risen slightly (+0.2 per cent) in the unvaccinated group. The authors concluded that annual influenza vaccination for HIV positive people may be harmful. They noted that since influenza has not caused excess morbidity in this group further evaluation of the practice of annual flu shot is warranted.15

It is important to note that in the study published in August a close look at the individual HIV RNA values shows that the viral load values declined for some of the vaccinated subjects and increased for some who did not receive flu vaccine even though on average the PCR increased with flu vaccination. This result is to be expected but points to the highly individual nature of HIV RNA infection. Each person should make an individual decision, in consultation with their health care provider.

Do you feel lucky? What is the risk of actually getting the flu? Are you healthy at this point in time? These are some of the points to ponder when considering a flu shot. The authors of the recent studies are clear that an influenza infection will have a negative effect on the immune system through viral stimulation just as much or more than a vaccination would. In fact the stimulation level with an actual flu infection would be much greater than the flu shot.16 For people with CD-4 counts below 100, it appears that a flu shot risks HIV stimulation with little benefit to be gained in increased immunity. Research does show with CD-4 counts above 100 that an effective immunity can be produced.13 It is possible that a person with counts in the 100-200 CD4 range with low HIV RNA values and taking an effective antiretroviral therapy could develop an effective level of immunity that might outweigh the risk of HIV stimulation.

Conclusion -- What to do

Flu Shots
(possibly other T-cell dependent vaccines as well)

Higher CD-4 counts( 300 or higher): Since the immunity level can be in the range of 80 percent or higher, flu shots are probably indicated. The negative effect of vaccination can be minimized if a person is taking an effective antiretroviral therapy.

Mid-range CD-4 counts( 100 to 300) Immunity levels can vary from 30 to 90 percent. The consensus at the ICAAC Conference was that flu shots are probably not indicated at CD4 of 200 and below. Other studies have suggested immunity is produced at CD-4 counts of 100 or higher. HIV asymptomatic individuals can be expected to develop effective antibody levels. HIV symptomatic individuals are likely to have a variable response to flu vaccine so that the decision becomes more individual. Antiretroviral therapy is important in reducing HIV stimulation produced by vaccines.

Lower CD4 counts(100 and below): The immunity produced is weak, morbidity with influenza in HIV-positive populations has not been confirmed and the risk of HIV stimulation is high. The drug amantadine hydrochloride can be effective in the prevention and treatment of disease caused by the influenza A virus.
Reduce exposure to the flu by vaccination of housemates, caregivers etc.

Hepatitus Vaccines

Protection against Hepatitis A and B is available. These vaccines should be used as early as possible in the course of HIV disease. Existing antibody levels should be checked prior to vaccination.

Tetanus/ Diphtheria

Boosters are recommended after any non-sterile wound if it has been more that ten years since the last vaccination. A more frequent interval is recommended if traveling to third-world areas.

These vaccinations may have a similar relationship to CD-4 count as listed for flu vaccinations.

All CD4 counts(the higher, the better) Since the effectiveness has been shown to much more independent of CD4 count and the protection level much higher than for flu shots pneumonia vaccination is still recommended. Most physicians feel there is a definite morbidity associated with pneumococcal infections (life threatening pneumonia).

Jon Hubert, DDS, is Cochair of the STEP Scientific Review Committee and a member of the Board of Directors of STEP.

Bibliography

Centers for Disease Control. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Prevention and control of influenza. MMWR. 1993;42: 1-10

A Review of the Conference on HIV Infection in Women

Pregnancy & Gynecological issues

On September 28, 1995, about 45 people attended a recent talk by two physicians who treat women affected by HIV. First, Dr. Watts discussed the epidemiology of the HIV pandemic. With 13 million people infected worldwide in 1993, and increasing proportion of these being women, especially in Asia & Africa, but also in the US, we need to get busy and learn how to care for them and their children. She pointed out the dual necessity of teaching internists about gynecological issues and gynecologists about HIV issues. All health care providers should offer HIV screening when a woman presents with pregnancy or any sexually-transmitted infection so that there is no delay in identifying HIV-positive women. The most common initial manifestation of HIV infection in women is yeast vaginitis (43% of the time in a study of 117 seropositive women), while 17% had acute retroviral syndrome with lymphadomegaly (large lymph nodes) and 15% had bacterial pneumonia as their first sign of illness.

Dr. Watts then discussed Human Papillomavirus (HPV) and cervical dysplasia (precancer of the cervix). While HPV is the most common sexually transmitted virus, present in about 50% of all women asymptomatically, it appears to be twice as common and 4 times more likely to lead to premalignancy in women with HIV, especially when CD4 counts are less than 200. Usually, dysplasia is easily treated when detected early, but women with HIV have more multicentric disease (cervical, perianal and on external genitalia), and also seem to have higher rates of recurrence after treatment. Currently, trials are attempting to answer questions about whether we need to do more intensive screening. For example, how often should HIV positive women have a Pap smear or colposcopy (looking at the cervix under magnification)? Furthermore, do we need treatments other than freezing and laser to limit recurrences of dysplasia? Accutane, a vitamin A cousin which is used to treat acne, is soon to be evaluated. Since all studies thus far have been cross-sectional (looking at one point in time), we need more information about progression and prognosis from longitudinal studies. For now, it makes sense for women with CD4 greater than 500 and no history of abnormal Paps to get yearly Pap smears and for those with CD4 less than 500 to get Pap smears every 6 months. Indications for colposcopy remain the same as for HIV-negative women. If dysplasia is found, it should be treated aggressively.

Dr. Watts reviewed the presentation of candidal (yeast) infections and pelvic inflammatory disease (PID) in women with HIV. Candida fungus seems to cause vaginal infections in women with CD4 above 500 which can be recurrent and recalcitrant. When the CD4 count is less that 200, oral yeast or thrush is common, and finally, esophageal involvement is seen when CD4 counts drop below 50. She recommended the use of ordinary vaginal creams and suppositories as first line treatment for yeast vaginitis and use of single dose fluconazole only when necessary (to avoid development of resistance). Topical versus oral prophylaxis is currently being studied. With regard to PID, both the incidence and severity is increased in HIV-positive women. The antibiotics used to treat PID remain the same, but there seems to be a greater number of women who require hospital admission for IV antibiotics and surgical drainage of abcesses.

Another gynecological problem sometimes seen in women with CD4 less than 50 is painful, erosive genital ulcers which are not caused by herpes or syphilis, but seem to be similar to apthous ulcers in the mouth. Like apthous ulcers, they are hard to treat, but often respond to steroids both topically and systemically, as well as antiretrovirals like Zidovudine (otherwise known as ZDV or AZT). A protocol using thalidomide is currently being evaluated.

In the area of HIV and pregnancy, there are a number of strategies for keeping the woman healthy, decreasing transmission to the infant, and keeping that infant healthy. One of the more positive studies of the last few years offers hope that fewer infants will be infected. ACTG 076 randomized women to receive placebo versus oral AZT during the third trimester, intravenously during labor and birth, and for the infant to receive oral AZT for the first 6 weeks after birth. The study was stopped early because the AZT treated mother-infant pairs had three times less transmission of the virus to the baby without significant complications or side effects. In the US, 84% of HIV-positive women are in childbearing years. 1.7/1000 women in the US are seropositive, and in Washington State .6/1000, with Seattle/King county area about 1/1000. In Washington state, two thirds of cases are due to heterosexual contact, and many of these women were unaware of their high risk contact, so screening based on history alone will miss up to half of the pregnant women with HIV. Dr. Watts argued that there should be no excuse for clinicians not to offer HIV screening, as this is at least as important and nearly as prevalent as many of the other infections or abnormalites we screen for routinely by amniocentesis such as neural tube defects and Down's syndrome.

Perinatal transmission of the virus to the infant occurs about 15-30% of the time, seeming to vary depending on the mother's CD4 count. In ACTG 076 the maternal-fetal transmisson rate was about 8% with AZT if the woman has not taken AZT in the past. Presence of p24 antigen as well as primary HIV infection during pregnancy seem to also affect vertical (mother to fetus) transmission rates. Viral RNA levels are currently being examined from the participants in ACTG 076 to determine another possible prediction of risk of transmisson from mother to fetus. A big question is when does the transmission occur? If we knew this, we could most effectively target treatment. There is evidence for both intrauterine (prior to birth) and intrapartum (at the birth) transmission found by looking for the virus in the placenta and products of conception, as well as by discordant twins. More often the first twin to be born is HIV -positive, probably due to greater exposure to maternal blood and secretions. It is thought from this and other evidence that probably 30-50% of transmission happens before the baby is born and 50-70% happens during the birth process. Cases of transmission after birth are rare since safe alternatives to breastfeeding are available and recommended in the US.

Current recommendations then, are that all pregnant women be offered HIV screening, and if positive, they then be offered AZT prenatally and during labor should they decide to continue their pregnancy. Counseling issues that will come up include prognosis both during pregnancy and in the long term. In the US, there is no clear acceleration of HIV illness during pregnancy nor is there an increase in pregnancy complications (except perhaps bacterial pneumonia and post partum infection), but still 50% of people will have AIDS within 10 years of infection. The HIV-positive pregnant woman should be on Pneumocystitis Carinii Pneumonia (PCP) prophylaxis if her CD4 count is less than 200 (and contrary to popular belief, Bactrim is safe during pregnancy). She should also be offered rifabutin MAC prophylaxis if her CD4 count is less than 50. Although there is not clear evidence to suggest that transmission occurs more in vaginal delivery than cesarean, early rupture of membranes and any instrumentation are to be avoided. Obviously, universal precautions should be employed during and after birth, and the infant should be washed before any shots or blood tests are performed. After birth, the woman needs good contraceptive counseling and support. She should be encouraged to use spermicide and condoms always, and consider another backup method such as hormones, diaphragm or tubal ligation (IUD is not recommended due to increased risk of PID). (Remember to watch for hormone interaction with other drugs such as rifampin which renders oral contraceptives ineffective.) Dr. Watts recommends that the infant receive Bactrim PCP prophylaxis starting at one month of life which can be stopped at about three months if HIV culture and PCR are negative. These children should be given injectable rather than oral polio vaccine to avoid any live virus. Overall, more advances in prevention have been made in pregnancy and newborn care than in most other areas of HIV work.

Dr. Currier discussed HIV in women more generally. She reviewed the magnitude of the pandemic, citing the grim projections that by the year 2000, 2 million women and 2.5 million children will die from HIV, and that 5 million children will be orphaned. In 1994, 18% of new AIDS cases in the US were in women. Additionally, survival of women with AIDS seems to be less than that of men in at least four different studies. Women are diagnosed at a lower CD4 count, and are treated less often with drugs such as AZT (50% of women, 80% of men) either because they weren't offered or because they refused. In the studies done so far, there seems to be more difference in access to care than in true biological gender differences in response to HIV.
In all studies, it is difficult to control for confounders of race, gender, sexual orientation, injectable drug use (IDU), socioeconomic level and stage of disease. In a Baltimore study of IDU's, more men had decreased platelet counts and more women had lower blood counts (hematocrits) probably due to menstruation. In another study of heterosexual IDU's there was no difference in survival one year after diagnosis of AIDS. Overall, women seem to have increased risk of toxoplasmosis, herpes and wasting syndrome, while men (especially gay) have a much higher incidence of Kaposi's sarcoma. In terms of medications and metabolism, there is very little information on differences between men and women. In 14 case reports of acute fatty liver, 12 were women, but the mechanism for this gender asymmetry is not understood. Studies of metabolism of AZT and other drugs such as oral contraceptives are underway.

Dr. Currier then reviewed the use of various antiretroviral agents. AZT does seem to provide some benefit for many people but it is time limited because of development of resistance. When someone has HIV but is asymptomatic, the best course is unclear. From ACTG 116A she recommends ddI when CD4 is less than 300, especially if the person has been on AZT more than 4 months. She also suggests that AZT in combination with ddC is better than AZT alone in some settings. D4t has not been looked at for initial treatment, but has been approved for patients intolerant of other drugs. Neuropathy is still a problem, and for women and small men, it is important to remember that there is a dose change for those weighing less than 132 lbs. This drug is easier to take because of its twice daily dosing and will likely be useful in combination. 3TC is still only approved for compassionate use, but seems to be quite effective at raising CD4 counts and decreasing viral load in combination with AZT without causing neuropathy. Although viral resistance to 3TC develops quickly, the mutation seems to keep the virus susceptible to AZT for at least one year. We are still awaiting clinical and survival data with the use of this combination. Dr. Currier also thinks a study looking at AZT/DDI versus AZT/3TC would be helpful. She lastly reviewed data from ACTG 175 trial which is detailed elsewhere in this issue.

Questions remaining include; How do we use viral load tests in clinical practice? Should combination therapy be initial treatment, or should we start one drug and then add to it? How does women's physiological response to HIV, and metabolism of various medications affect these questions?

Though neither of these speakers had time to discuss prevention of HIV in women, we must remember that outreach and education, especially to women of color whom the epidemic has affected disproportionately, must remain a strong focus for anyone in the field.

Sarah Huffbauer is a family physician practicing at Country Doctor Community Clinic here in Seattle.

Review of Viral Load and Combination Therapy Data

by J. Mark Bray

The 35th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICCAC) was held in San Francisco September 17-20, 1995. The purpose of this conference is to review the progress being made in the treatment of infectious diseases. Many of the presentations focused on new antibiotics and their uses. However, about one fifth of the over 1,800 presentations were related to AIDS.

AIDS research and new treatments received more attention than in previous years due to the fact that the International Conference on AIDS has begun a two year schedule. (The last International AIDS Conference was in 1994 in Yokohama, Japan and the next International AIDS Conference will be in Vancouver, British Columbia, June of 1996.)

ICCAC brought together a variety of different scientists, researchers, health care providers, treatment information specialists, activists and people living with infectious diseases.

This article will review some of the research presented that relates to HIV viral load studies and combination therapy. In the article that follows, Dr. Jeff Schouten will review all the data presented at ICCAC on the new class of drugs, protease inhibitors.

Dr. David Ho, of the Aaron Diamond AIDS Research Center in New York, presented more findings from his research groups' observations on HIV's infectious cycle. By examining the blood of men and women taking the Abbott protease inhibitor, ritonavir, Dr. Ho was able to demonstrate that on the average at least 10 billion HIV particles are produced daily. The lifespan of these new free virions is about eight hours before they begin to infect CD4 cells. Once the CD4 cell has been infected it will live for about 2.2 days before it dies. Dr. Ho went on to postulate that given this information the new virus will begin making more copies of itself in about 1.2 days. With such a fast level of replication it seems possible that the virus will create many more mutations of itself than previously thought possible.

Dr. Ho stated that "any single mutational change probably occurs multiple times per day in a given human being, and copies of a single HIV gene with multiple mutations probably occur as well in the course of a day." What this means is that with all those mutations, the amino acid sequence and shape of the HIV enzyme will cause a decrease or in some cases halt antiviral drugs from working.

The rapidly evolving virus may be why HIV eventually defeats the immune system, according to Dr. Steven Wolinsky of Northwestern University, who also gave a lecture at the opening session of the conference. Dr. Wolinsky pointed out that the immune response depends on certain proteins produced by HIV being present in order for cytotoxic lymphocytes (CTL's) to recognize cells as being infected with HIV and kill them. With so many different mutations, it is possible that the specific proteins will not be expressed and the CTL's may not recognize the HIV- infected cells as being infected.

Dr. Ho's answer to the problem of multiple mutations and HIV variation demonstrated the interest of many practitioners in combination therapies. "We need combinations of drugs that force the virus to mutate at multiple, preferably more than four, sites." In that statement Dr. Ho was describing the use of combination therapy to decrease drug-resistant strains of HIV by both reducing HIV replication and increasing the number of sites at which HIV will need to mutate in order to produce more HIV virions.

ACTG 175

One of the most important AIDS research studies presented at ICAAC was ACTG 175, a study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID)(abstract LB-01).

ACTG 175 enrolled over 2,400 volunteers and lasted for two years. People were randomized to one of four treatments: Zidovudine (ZDV, AZT) alone, ddI alone, ZDV plus ddI, or ZDV plus ddC. Three different types of outcomes were evaluated; 1) survival; 2) a clinical endpoint consisting of either progression to AIDS or death; and 3) fifty percent or greater drop in CD4 count. The study population included people who had never had any antiviral therapy and people with previous ZDV therapy. The trial also included a higher proportion of women, African-Americans, Hispanics, and injection drug users than previous ACTG trials.

If persons were doing poorly (poorly being defined as the development of an AIDS-related condition or a fifty percent fall in CD4 counts), they were switched to a different type of drug therapy. Those randomized to single drug therapy were switched to combination therapy and those already taking combination therapy were switched to the other combination. This allowed for a comparison of immediate versus delayed combination therapy.

By the end of ACTG 175 about one half of the volunteers had stopped taking their medications. Only seven percent of these people stopped due to severe problems related to the drugs they were taking. The remainder of this group stopped their medication for a variety of reasons such as milder adverse events, CD4 decline (less than 50% decrease) or due to the large number of pills that had to be taken. (This was a double blind, randomized, placebo controlled study so everyone had to take the same number of pills every day.)
The overall finding of the study was that ddI alone, ddI plus ZDV and ddC plus ZDV was each superior to ZDV alone in preventing one or more serious consequences of HIV infection including CD4 decline. This result was observed whether or not the participants had been previously treated with ZDV.

For those that had never taken ZDV, the combination of ZDV plus ddC seemed to work best. This group showed a decrease in disease progression to AIDS or dying and progressing to a 50% or greater decline in CD4 count or AIDS or death. ZDV monotherapy had less response than all other regimens as initial therapy.
The combination of ZDV plus ddI worked best in slowing disease progression and slower progression of CD4 decline for participants who had taken ZDV before the study. ZDV monotherapy came out less favorable than the other 3 regimens for those who had already taken ZDV.

In addition to this study, a smaller or sub-study was included in ACTG 175 that examined viral load in 348 volunteers at intervals of 8, 20, 56, 80 and 104 weeks; 196 people were in the antiviral naive group and 152 were antiviral experienced. Virus level was measured by several different assays, but only plasma HIV RNA was presented at ICAAC.

Antiviral naive participants in the combination therapy arm saw the greatest reduction in viral load with ZDV plus ddC. Those in the antiviral experienced group saw the same decrease in HIV RNA in all treatment groups. No exact numbers were given at ICAAC; instead only group findings were used.

Overall a 0.7 log (7 fold) decrease was seen in the two combination study groups that was sustained for the first year of this study. Data beyond the one year marker was not available at the time of the ICAAC presentation.

After ACTG 175 a second study known as Delta, a European and Australian Cooperative trial, has been released. The Delta trial compared ZDV to ZDV plus ddI and ZDV plus ddC in ZDV naive (Delta I) and ZDV experienced participants (Delta II) with CD4 counts between 50 and 350.

In the Delta I study group of ZDV naive people, either ZDV plus ddI or ZDV plus ddC was superior to ZDV monotherapy. In the Delta II group of ZDV experienced participants all drug regimens appeared equal in efficacy in slowing disease progression. Overall ZDV plus ddI and ZDV plus ddC were superior to ZDV monotherapy.

ACTG 175 and the Delta studies show that monotherapy is less effective in treating HIV/AIDS than combination therapy. Combination therapy, whether for antiviral naive or experienced, based on these results, is being used more often as primary therapy for people living with HIV/AIDS.

However, long term survival benefits have yet to be approved for combination therapy.

J. Mark Bray is on staff at STEP as its Treatment Information Specialist.

Protease InhibitorsAn Update from the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy

by Jeffrey T. Schouten, M.D.

The list of protease inhibitors currently in clinical trials or soon to begin clinical trials is expanding rapidly. Unlike reverse transcriptase inhibitors, protease inhibitors are a very diverse group of compounds. Presentations at the ICAAC Conference, in September 1995, discussed 10 different protease inhibitors. Hoffman-La Roche applied for FDA approval for InvaraseTM (saquinavir, and formerly RO 31-8959) on September 5, 1995. Therefore the first of several protease inhibitors should be available for general prescription use before the end of 1995. Already several other protease inhibitors are available through lottery programs. Protease inhibitors block an HIV-1 enzyme critical for the production of new viruses. Thus, unlike nucleoside analogs, protease inhibitors inhibit HIV production in newly and chronically infected cells. Very dramatic decreases of viral RNA levels are seen within a few weeks of protease inhibitor administration (up to 99%); however , resistance develops rapidly to monotherapy. Thus, several current studies are evaluating combinations of protease inhibitors and nucleoside analogs with very encouraging results, as discussed later in this article.

The following is a list of protease inhibitors currently in Phase I or II clinical trials:

RitonavirTM (ABT 538)

IndinavirTM (MK 639, L-735-524)

InvaraseTM (saquinavir, RO 31-8959)

AG 1343 (Agouron Pharmaceuticals)

U-103017 (Upjohn Pharmaceuticals)

VX 478 (Vertex Pharmaceuticals)

The following protease inhibitors are newly identified and may soon begin clinical testing:

CGP 53 437 (Ciba Geigy Pharmaceuticals)

CGP 57 817 (Ciba Geigy Pharmaceuticals)

KNI-272 (Kyoto Pharmaceuticals)

A-80978 (Abbott)

Several trials of protease inhibitor monotherapy were presented at ICAAC.

1. AG 1343 was studied in 22 people with CD4 >200 and Viral RNA >20,000 at two doses, 900 mg and 1200 mg for 28 days. The drug was well absorbed orally and it was well tolerated. At the 900 mg dose, there was a decrease in viral RNA >1 log (ten times) in 20% of the participants compared with 33% at the 1200 mg dose. CD4 counts increased more than 150 in 60% of persons at the 900 mg dose and 33% at the 1200 mg dose.

AG 1343 was evaluated in another study at three doses, 1000, 1200, and 1500 mg in a total of 30 persons. A greater than 1 log (ten times) decrease in viral RNA was seen in 21/30 participants at 28 days, and the maximum median decrease was between 1.4-1.7 logs.

A dose escalation study of InvaraseTM (saquinavir, RO 31-8959) was conducted in 40 people which showed that the higher dose, 7200 vs. 3600 mg, resulted in less resistance and only a few more minor side effects. At 24 weeks, there was a mean increase in CD4 cells of 100 at the higher dose compared to 31 at the lower dose, and the sustained decrease in viral RNA was 0.9 logs (almost 10 times decrease) at the higher dose compared to 0.5 (5 times decrease) for the lower dose.

Another studied examined the specific sites of mutation in HIV which caused resistance to InvaraseTM (saquinavir) and found that the mutations also conferred resistance to two other protease inhibitors, Ritonavir TM (ABT 538) and IndinavirTM (MK 639, L-735-524). Also, one mutation conferred resistance to most other protease inhibitors. These studies are important when designing trials to evaluate combinations of protease inhibitors, so that non-cross resistant drugs can be combined to achieve maximal long-term inhibition of HIV replication.

Another report evaluated the resistance patterns for Ritonavir TM (ABT 538), identifying the specific amino acid substitutions which caused HIV-1 resistance to this drug. Again, this data is important for future study design.

CGP 53 437 and CGP 57 817 are related protease inhibitors developed by Ciba Geigy Pharmaceuticals which have good oral absorption in mice models. In a unique trial, CGP 53 437 was administered to healthy HIV-negative people and then the compound was isolated from their blood and tested in the test tube to see if it still inhibited HIV reproduction. This may be a useful method to screen future compounds for effectiveness in humans. Clinical trials will start soon on these compounds.

KNI-272 has only been studied in mice to date, where it blocked HIV replication in all tissues, except the spleen.

VX-478 is entering clinical trials and the sites of mutation conferring resistance have been identified, again useful for selecting protease inhibitor combinations for future trials.

Merck reported on new analogs (similar compounds) of Indinavir TM (MK 639, L-735-524) which appear to be more potent than the parent compound.

Parke-Davis reported on computer models which have designed new protease inhibitors, based on U-103107. These new compounds will begin animal testing soon.

Upjohn has conducted Phase I studies of U-103017, in single increasing doses from 100-2000 mg. The drug is well tolerated, has good absorption in the solution form, and has a half-life of 8-18 hours. It also appears to be synergistic (enhanced effect) with Zidovudine (ZDV or AZT) and is effective against ZDV-sensitive and resistant clinical isolates of HIV.

Several trials studying combination trials with protease inhibitors were also presented at ICAAC.

A multicenter trial compared Zidovudine (ZDV )(600 mg), ZDV + Indinavir TM (MK 639, L-735-524)(2400 mg), and Indinavir TM (MK 639, L-735-524). A total of 74 persons were enrolled and treated for 24 weeks. Eligibility criteria were CD4 <200 and viral RNA >20,000. At 24 weeks, CD4 counts were 50 cells higher in the ZDV + Indinavir, and Indinavir groups compared to the ZDV group. Also, at the end of the trial there was a 2.5 log (25 times) decrease in viral RNA in the ZDV + Indinavir TM group, a 1.5 log (15 times) decrease in the Indinavir group, and only a 0.3 (3 times) decrease in the ZDV group. Thus, in this relatively short-term trial, the combination of Zidovudine plus Indinavir appeared advantageous over either drug alone.

An extension of a previous trial was reported comparing a triple drug combination, Invarase TM (saquinavir, RO 31-8959)(Saq) + Zidovudine(ZDV) + Zalcitabine (ddC), to Saq + ZDV, and ddC + ZDV. Following the initial 24 weeks of this trial, people were continued on the therapy for 12-24 weeks in a blinded fashion. 73% completed the extension trial. After 48 weeks of therapy, CD4 counts above baseline were observed in 51% of persons receiving all 3 drugs, compared to 33% in the other two groups. Also, the triple drug combination resulted in a decrease in viral RNA of 0.5 log (5 times), compared to less than 0.25 logs (2.5 times) in the other groups. Thus, the triple drug combination appeared to be more effective in inhibiting HIV viral replication over the 48 weeks of this trial. More triple drug trials are currently underway.

Ritonavir TM (ABT 538) has been reported to cause a 99% decrease in plasma viral RNA during the first two weeks of therapy, but resistance develops rapidly when it is administered alone. The combination of Ritonavir TM and Invarase TM (saquinavir, RO 31-8959) was studied in a rat model because the resistance to one of these drugs does not cause resistance to the other. It was found that Ritonavir significantly increased the absorption of Invarase, which is a problem with Invarase. Therefore, the combination of these two protease inhibitors is exciting because it has a 2-fold advantage, both increasing the absorption of Invarase and the lack of overlapping drug resistance.

The effect of simultaneous drug administration is a concern in all drug trials, partly because of overlapping toxicities and also the effect of each drug on the absorption and metabolism of the other. The combination of Ritonavir TM (ABT 538) and Zidovudine (ZDV) was evaluated and it was found that while Ritonavir blood levels were not changed by added ZDV (600 mg), Ritonavir (1200 mg) caused a lowering of ZDV blood levels, but only by little, so no dose adjustments are needed when these two drugs are combined at the doses studied.

Fluconazole was reported to increase blood levels of Ritonavir TM (ABT 538), but the increase was minor (<15%) and no dose adjustments were recommended.

The interaction of Interleukin-2 (IL2) and Indinavir TM (MK 639, L-735-524) was studied in 24 people with CD4 <300 in a complex trial comparing MK 639 (2400 mg daily) to, IL2 (12 million units/day for 5 days every 2 months) + MK 639 (2400 mg daily), and IL2 + MK 639 (2400 mg/day for 10 days every 2 months coinciding with IL2). In prior trials, IL2 has been shown not to be very effective in persons with less than 200 CD4 cells. The current trial found only a minimal effect from IL2, the results after 2 cycles of IL2 (4 months) were as follows; mean CD4 count in the MK 639 group was 251, compared to 263 in the IL2 + continuous MK 639, and 222 in the IL2 + intermittent MK 639. The authors stated that "further observations and infusions are required for clarifications of any IL2 effect."

All of the above reports used surrogate markers as end points in the studies. None of the above studies correlated the changes in surrogate markers with clinical events, outcomes, or survival. The use of surrogate markers allows for much more rapid results of possible drug efficacy; however, the ultimate measure of efficacy is still how clinical outcomes are altered. For all of the protease inhibitors studied above, the effect on clinical outcomes is still pending. However, it is clear that many new protease inhibitors are entering clinical trials with some very dramatic results on surrogate markers, sustained for up to one year in some of the combination trials. Many more trials are needed to evaluate various double and triple-combination therapies. (For detailed information concerning any of the above reported trials please call the STEP Treatment Information Hotline at (206) 329-4857 or 1-800-869-7837 or you can e-mail us at step@lifelongaidsalliance.org.)

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